Use of 3-amino-n-carbamylpyrazoles as analgesic agents



United States Patent 3,362,877 USE OF 3-AMINO-N-CARBAMYLPYRAZOLES ASANALGESIC AGENTS Clifford L. Dickinson, J12, Wilmington, Del., assignorto E. I. du Pont de Nemours and Company, Wilmington, Del., a corporationof Delaware No Drawing. Original application May 31, 1963, Ser. No.284,323, now Patent No. 3,274,203, dated Sept. 20, 1966. Divided andthis application June 10, 1966, Ser. No. 556,540

16 Claims. (Cl. 167-65) R NHR I N I R1 R:

which can exist as the isomeric formula R;:NHR3

NC-N R 1R: H

where:

X is oxygen or sulfur;

R is methyl;

R is alkyl of 1 through 6 carbons where the alkyl is joined to thecarbamyl nitrogen by a primary or sec ondary carbon of the alkyl group;alken-Z-yl of three through 6 carbons where the alken-2 yl group isjoined to the carbamyl nitrogen by a primary or secondary carbon of thealken-Z-yl group; alkoxyalkyl of 2 through 6 total carbons; hydroxyalkylof 2 through 6 carbons; dimethylamino; or dialkylaminoalkyl where eachof the alkyl groups in the dialkyl portion has 1 or 2 carbons and theremaining alkyl group has 1 through 4 carbons with a total of from 3through 7 in the dialkylaminoalkyl group; and Where R and R can bejoined together and together with the carbamyl nitrogen form aheterocyclic structure from the following group:

morpholino, i.e. N O

pyrrolidino, i.e. N

. pipendino, 1.6. N

. dehydropipendmo, Le. N

3,362,877 Patented Jan. 9, I968 azabicyclononidino, i.e. N\ Omono-substituted piperidino of the structure where Y is H or CH Y is H,CH C H or COOR where R is alkyl of 1 through 4 carbons, and Y, is H,alkyl of 1 through 6 carbons, hydroxyalkyl of 2 through 6 carbons,trifluoromethyl, COOR Where R is alkyl of 1 through 4 carbons,dialkylaminoalkyl of 3 through 7 carbons where each of the alkyl groupsin the dialkyl portion has 1 or 2 carbons and the remaining alkyl grouphas 1 through 4 carbons, pyrrolidinoethyl or arylalkyl of 7 through 9carbons including such groups as benzyl, phenethyl, and o-, mandp-tolylethyl; and disubstituted piperidino of the structure Y2 where:

Y and Y have the same meaning as above;

R can be hydrogen but it is much more highly preferred that it is anacyl radical of 1 through 3 carbons such as formamido, acetamido andpropionamido; and

R is hydrogen; halogen such as fluorine, bromine and most preferablychlorine; alkyl of 1 through 3 carbons and preferably methyl; ortrifiuorornethyl.

Of the compounds of Formula 1 Where R is alkyl or alken-Z-yl, it ispreferred that the alkyl or alken-Z-yl group is joined to the carbamylnitrogen by a secondary carbon of the alkyl or alken-Z-yl group.

The compounds of this invention are generally solids. They can be usedas inhibitors for vinyl polymerization but are particularly useful fortheir physiological characteristics.

Because of their excellent analgesic activity and other desirablepharmacological properties, the preferred compounds of Formula 1 arecarbamyl pyrazoles where X is oxygen and where R and R are joined toform a piperidino ring and in particular a mono-substituted piperidinoring Where the substituent is in the para position with respect to thecarbamyl nitrogen. Thus, preferred compounds of this invention includethe following exemplary ones:

1-N-(4-methylpiperidino) carbonyl-3 (5) -formamido- 4-chloropyrazole1-N-(4=methylpiperidino)carbonyl-3 5 -formamido-4- methylpyrazole l-N-(4-methylpiperidino carb onyl-3 5 -acetamido-4- chloropyrazole1-N-(4-methylpiperidino) carbonyl-3 (5) -acetamido-4- methylpyrazole1-N-(4-methylpiperidino) carbonyl-3 (5) -propionarnido- 4-chloropyrazole1-N-(4-methylpiperidino) carbonyl-3 5) -propionamido- 4-methylpyrazoleAlso preferred are those compounds of Formula 1 Where R is alkyl of 1through 4 carbons, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, etc. Illustrative of these preferred compounds are thefollowing: 1-N,N-dimethylcarbamyl-3 (5 -formamidopyrazole 3 (5-acetamido-1-N,N-dirnethylcarbamylpyrazole1-N-methyl-N-isopropylcarbamyl-3 -formamidopyrazole 3 (5-acetamido-1-N-methyl-N-isopropylcarbamylpyrazole1-N-sec.butyl-N-methylcarbamyl-3 (5 -formarnidopyrazole 3 (5-acetamido-1-N-sec-btuyl-N-methylcarbamylpyrazole The substitutedcarbamyl pyrazoles of this invention can be prepared by reaction of theappropriate pyrazole with selected reactants as more fully describedbelow.

When the starting material is a 3-formamidopyrazole compound, thislatter compound can be prepared by refiuxing the 3-aminopyrazole in98lO0% formic acid for at least hours, removing the formic acid, andboiling the resulting product in water for 4 or more hours. The3-acetamidopyrazoles and B-propionamidopyrazoles are prepared by heatingthe 3-aminopyrazole with the appropriate anhydride for an hour, removingthe excess anhydride and acid, and boiling the product for 4 or morehours.

The 4-alkyl-3-aminopyrazoles can be prepared by condensing 1 mole of theappropriate nitrile (propionitrile for methyl as the 4-alkyl) with 1mole of ethyl formate using 1 mole of sodium ethoxide in ethanol to givethe sodium salt of 2-formylpr0pionitn'le. This latter compound iscondensed with a mole of hydrazine hydrochloride by heating under refluxto obtain 3-amino-4- methylpyrazole.

3-amino-4-trifluoromethylpyrazole is prepared by treating a solution of3-aminopynazole4-carboxylic acid in hydrogen fluoride with sulfurtetrafluoride at 200 C. for at least 6 hours.

One general method for the preparation of the pyrazoles of thisinvention can be carried out where the amine-N-carbonyl chloride (e.g.,N,N-dimethylcarbamoyl chloride) is available. In this process there arebrought together approximately equimolar amounts of the pyrazole and thechloride in an unreactive solvent such as ether, ethyl acetate, orbenzene, together with an equimolar amount of a base such as sodiumhydride or triethylamine. The resulting mixture is refluxed for anextended period, say up to about 24 hours or more, and allowed to cool.The insoluble chloride, e.g. sodium chloride or triethylaminehydrochloride, is filtered off and the solvent is removed from thefiltrate to give the desired carbamyl or thiocarbamyl pyrazole product.

The same general procedure as just described is used when thepyrazole-l-carbonyl chloride is available (e.g., from pyrazole havinghydrogen on nuclear nitrogen and either phosgene or thiophosgene) exceptthat the seconary amine is reacted with the pyrazole carbonyl chloride.The first method is preferred if the 3-aminopyrazoles are used since theB-amino group would react with the phosgene or thiophosgene, whereas thesecond method is preferred for amines such asN-methyl-N-hydroxyethylamine where the amine substituent can also reactwith the phosgene or thiophosgene.

The amine carbonyl chlorides such as N-piperidine carboxyl chloride areprepared by placing a flask fitted with a Dry-Ice condenser, mechanicalstirrer and dropping funnel preferably at least 1.2 moles of phosgene inan inert solvent such as ether, tetrahydrofuran, benzene, ethyl acetateor the like. A solution of 1 mole of the selected amine, e.g.,piperidine, and preferably, for increased yields, with 1 mole oftertiary amine such as triethylamine, in the selected solvent is addedslowly with stirring and the temperature is kept below C. withoccasional cooling. When all of the amine has been added, the mixture isstirred several hours. The mixture is filtered to remove thehydrochloride and the solvent is removed from the filtrate by boiling itoff. The remaining amine-N-carboxyl chloride is distilled under reducedpressure to effect purification.

Alternatively, the py-razole can be used in the above procedure in placeof the amine (piperidine). By this procedure, with B-acetamidopyrazole,one obtains 3-acetamidopyrazole-l-carbonyl chloride.

As mentioned above, the compounds of this invention have outstandingactivity as analgesics, many of them exceeding codeine in potency, asshown by standard animal tests, e.g. the Hot Plate Test in mice and theRadiant Heat Tail Flick Test in rats. This analgesic activity in thesecompounds is particularly valuable because of significantly favorabletherapeutic ratios. General painkilling benefits, as Well as otherphysiological beneficiation associated with aspirin, are believed to beobtainable according to this invention based on tests and evaluationthus far carried out.

In pharmaceutical application a compound of this invention will beadministered to the body orally, parenterally and by other methods. Thedosage will vary and will depend on such factors as the condition beingtreated; age and weight of the recipient; the responsiveness of therecipient; prior, concurrent and intended subsequent, medication andtreatment, general health of the recipient; frequency of treatment; andof course the purpose and nature of the effect desired.

Generally speaking, the active compound will be administered to awarm-blooded animal in a physiologically beneficial amount.Administration can be in a single dose or in a plurality of doses overan extended period of time. It will furthermore be understood that everycompound within this invention does not have an identical level ofdosage requirement for therapeutic or prophylactic eifectiveness andtherefore experts will understand that some dosage variation betweencompounds can be expected for maximum benefits. It will of course alsobe understood that an initial dose, or first group of doses, in a courseof treatment can be in greater amounts, if appropriate, for a particularmedical situation and a rapid response is sought by the earlyadministration of relatively large doses and thereafter the minimallyeffective dosage, or maintenance dosage, is determined.

A single dose will rarely exceed about 400 or 500 millgrams of activecompound within this invention, although larger amounts can be used ascalled for in any given situation. Extremely small doses will effectsome benefit but at a practical matter a single dose of less than about1 or 2 milligrams will seldom be used. For treating small animals withhigh physiological response and using highly active compounds, routineusage can be at much lower dosage levels however. Doses can be repeatedin the same or greater or lesser amounts over a period of time as longas improvement in the recipient is observed or as long as needed underthe circumstances.

The active compound will ordinarily be administered with a non-toxicpharmaceutical carrier in a variety of practical dosage forms. Thesedosage forms are novel compositions comprising the non-toxicpharmaceutical carrier and a physiologically beneficial amount of one ormore active compounds of this invention. These highly useful dosageforms constitute an important aspect of the present invention.

' Suitable non-toxic pharmaceutical carriers or vehicles include liquidssuch as water, aromatic water, alcohols, syrups, elixirs, pharmaceuticalmucilages, such as acacia and tragacanth, oils such as of petroleum,animal, vegetable or synthetic origin, for example, peanut oil, soybeanoil, fish oil such as cod liver oil, or the like, for oraladministration; water, saline, aqueous propylene glycol, aqueouspolyethylene glycol, aqueous lactose, aqueous maltose, aqueous glucose(dextrose), aqueous sucrose, or the like, for administration byinjection. Suitable solid carriers include soft gelatin capsules, hardgelatin capsules, slow or delayed release pills or capsules, powders,tableting vehicles and the like. Suitable solid or liquid non-toxicpharmaceutical carriers are well known in the art and the selection ofcarrier can be from those appropriate and available in accordance withWell known prescription techniques. The compositions of this inventiontherefore include such dosage forms as solution, suspensions, syrups,elixirs, tablets, capsules, powder packets, and the lke.

A vast number of suitable pharmaceutical carriers are 5 liquid medium,the concentration will ordinarily be in the range from about 0.5 to 5.0%by weight of active ingredient. For injection concentrations from 2 toare satisfactory. In tablets, powders, capsules and the like the amountof active ingredient may if desired be as much as 90 to 95% or more byweight of the total composition. 20

The amount of pharmaceutical carrier in the novel compositions willgenerally be in the range of from 5 to 95% by weight and preferably fromto 90% by weight.

The active compounds of this invention can be formu- 25 lated if desiredwith one or more pharmaceutically active materials for combinationefiects, treatments and benefits. Such materials include but are by nomeans limited to vitamins, pain killers, tranquillizers, antibiotics,antitus- Analysis.Calcd. for C H N O: C, 48.0; H, 5.6; N, 33.6. Found:C, 48.2; H, 5.8; N, 34.0.

To a stirred mixture of 3.0 grams of 3-acetamidopyrazole and 10milliliters of water is added 4.0 grams of bromine. After three hours,the solution is made neutral with 10% sodium hydroxide and after sometime a precipitate of 3-acetamido-4brom0pyrazole is collected (yield 3.3grams). It is recrystallized from ethyl acetate, M.P. 144.5-145.5 C.

Analysis.Calcd. for C H N OBr: C, 29.4; H, 3.0; Br, 39.2. Found: C,30.7; H, 2.8; Br, 37.5.

The 3(5) acetamido-4-bromo-1-N,N-dimethylcarbamylpyrazole of thisexample exhibits an outstanding analgesic activity. The compound isformulated conveniently as an injectible solution of 1%, 2%, 5% and 10%by weight concentration in a mixture of 10% ethanol and 20% propyleneglycol in isotonic saline; and in 5, 10, and 25 milligram amounts instandard two-piece sealed hard gelatin capsules, as well as in softgelatin capsules, for oral administration. In pharmacologicalapplication it is administered in these dosage forms at dosage levels inthe range of 5-100 milligrams.

The general procedure of the preceding example is repeated, using4-bromo-3-acetamidopyrazole as the pyrazole reactant as in that example,and substituting on a molar basis equivalent amounts of the followingindicated amine-N-carbonyl chlorides for the dimethylcarbamyl chlorideof that example, to obtain the following listed exemplary compounds ofthis invention:

Example No. Amine-N-carbonylchloride Product N-methyl-N-nhexylcarbamoylchloride N-rnethyl-N-(penten-2-yl) carbamoyl chloride.N-methyl-N-(2-hydroxyethyl)-carbamoyl chloridN-rnethyl-N-methoxymethylcarbamoyl chloride.

N -methyl-N-n-propylcarb amoyl chloride N-methyl-N-allylcarbamoylchloride N-methyl-N-methoxyethylcarbamoyl chloride N-methyl-N-methoxypropylcarbamoyl chloride. N-methyl-N-dimethylaminocarbamoyl chlorideN-methyl-N-diethylaminoethylcarbamoyl chloride-..

N-methyl-N-isobutylcarbamoyl chloride I: u

N methyl-N-ethylcarbamoyl chloride3-aceta1nido-4-bromo-l-N-methyl-N-ethylcarbamylpyrazole. N-methyl-Nisopropylcarbarnoyl chloride 3-aeetamido-4-bromo-l-N-methyl-N-isopropylcarbamylpyrazole.N-methyl-N-seebutylcarbarnoyl chloride-3-acetamido-4-bromo-1-N-methyl-N-sec-butylcarbamylpyrazole.

3-acetamidei-brOmo-1-N-1nethyl-N -n-liexylcarbamylpyrazole.

3-acetamido4-bromo-1-rnetl1yl-N-(penten-Q-yl) carb amylpyraz ole.3-acetamido-4-bromo l-N-methyl-N-(2hydroxyethyl) carbamylpyrazole.3acetamido-4-bromod-N-methyLN-methoxymethylcarbamylpyrazole.

3-acetamido-4-bromo-1-N-methylN-methoxypropylcarbamylpyrazole.3-acetamido-tbromo-l-N-methyl-N-dimethylaminocarbamylpyrazole.3-acetarnid0-4-brorno-l-N-Inethyl-N-diethylaminoethylcarbamylpyrazole.3-acetamido-4-bromo-1-N-methyl-N-n-propylcarbamylpyrazole.3-acetamido-4-brorno-LN-methyl-N-isobutylcarbamylpyrazole.3-acetamido-4-bromo-l-N-rnethyl-Nallylcarbamylpyrazole.

3 acetamidoA-bromo'l-N-methyl-N-methoxyethylcarbamylpyrazole.

sive agents, etc. The compositions can of course contain suitablepharmaceutical modifiers such as coloring agents, sweetening or otherflavoring agents, solubilizing agents, etc. as will readily occur topersons skilled in this art.

This invention will be better understood by reference to the followingillustrative examples in which parts and percentages given are by Weightunless otherwise indicated:

Example 1.3 (5 )-acetamid0-4-br0mo1-N,N- dimethylcarbamylpyrazole Amixture of 10.2 grams of 4-bromo-3-acetamidopyrazole and 2.3 grams ofsodium hydride in 100 milliliters of tetrahydrofuran is stirred andrefluxed 15 minutes. N,N-dimethylcarbamoyl chloride (5.6 grams) is addedand the mixture refluxed two hours. The mixture is filtered and thefiltrate concentrated to give 13.6 grams of 3(5)-acetamido-4-bromo-1-N,Ndimethylcarbamylpyrazole. Recrystallization from benzene gives a meltingpoint of 124 125 C.

Analysis.Calcd. for C H N o Br: C, 34.9; H, 4.0.

Found: C, 35.6; H, 4.0.

The 3-acetamido-4-bromopyrazole is obtained by the following procedure:

A solution of 16.6 grams of 3-aminopyrazole in milliliters of aceticacid and 40 milliliters of acetic an- 7 The preceding Examples 1-15 canbe repeated using a similar amount of corresponding thiocarbamoylchloride reactant in place of the indicated carbamoyl chloride reactantto obtain the corresponding thiocarbamylpyrazole products.

Similarly, the preceding procedures can be repeated using thecorresponding 4-chloro, 4-fluoro, 4-alkyl and 4-trifluoromethylcarbamoyland thiocarbamoyl chloride reactants in place of the indicated carbamoyland thiocarbamoyl chloride reactant to obtain the correspondingcarbamylpyrazole and thiocarbamylpyrazole products.

Similarly, the preceding examples can be repeated using correspondingcarbamoyl and thiocarbamoyl chloride reactants having only hydrogen inthe 4-position to obtain the corresponding 4-unsubstituted carbamylpyrazole and thiocarbamylpyrazole products, as illustrated by thefollowing:

Example I 6 .-3 -ac tamid0-] -N,N -d imeth ylcarbamylpyrazole A mixtureof 12.5 grams of 3-acetamidopyrazole and 4.7 grams of sodium hydride(53%) in milliliters of the dimethyl ether of ethylene glycol arestirred and refluxed 30 minutes. N,N-dimethylcarbamoyl chloride (10.7grams) is added and the mixture refluxed overnight. The mixture isfiltered and the filtrate evaporated to dryness. The solid remaining isrecrystallized from benzene to give 12.5 grams of1-N,N-dimethylcarbamyl- 7 S-acetamidopyrazole, M.P. 122124 C.

Analysis.Calcd. for C l-1 N C, 49.0; H, 6.2; N, 28.6. Found: C, 48.0; H,6.2; N, 28.8.

The compound is formulated and used in 25, 50 and 100 milligram amountsin standard two piece hard gelatin capsules for oral administration. Thecompound is formulated conveniently as injectible solutions of and byweight concentration in isotonic saline; and as injectible solutions in5% and 10% by weight concentrations in an aqueous solution containingalso 5% dextrose.

Example 1 7.-3-amin0-1-N,N-dimethylcarbamylpyrazole A mixture of 17.0grams of 1-N,N-dimethylcarbamyl- 3(5) (pdimethylaminobenzalamino)pyrazole, 12.5 grams of2,4-dinitrophenylhydrazine, and 0.5 gram of p-toluenesulfonic acid in200 milliliters of ethanol are refluxed 30 minutes, cooled in ice, andfiltered. The filtrate is concentrated, dissolved in 150 milliliters ofwater, treated with decolorizing charcoal, and extracted overnight withchloroform in a continuous extractor. The chloroform extract isconcentrated to give 6.4 grams of 3 (5-amino-1-N,N-dimethylcarbamylpyrazole, M.P. 59- 62 C., which uponrecrystallization from cyclohexane has a melting point of 63-64 C.

Analysis.Calcd. for C H N O: C, 46.7; H, 6.5; N, 36.4. Found: C, 47.1;H, 6.4; N, 36.2.

This compound can be formulated in 10% by weight concentration inisotonic saline solution. Dosage of 50- 100 milligrams as needed can beadministered for analgesic treatments.

Example 18.-1-N,N-dimethylcarbamyl-3- formamz'dopyrazole A solution ofgrams of 3-aminopyrazole in 50 milliliters of 98% formic acid is heatedunder reflux overnight (16 hours). The formic acid is removed underreduced pressure (7 mm.) and the residue is refluxed in 100 millilitersof water for six hours. This is cooled and the precipitate of3-formamidopyrazole is collected to yield 10.0 grams, M.P. 160-161 C.

A mixture of 5.7 grams of 3-formamidopyrazole, 2.4 grams of sodiumhydride (53% in mineral oil) and 5.3 grams of N,N-dimethylcarbamoylchloride is stirred and heated under reflux overnight. The mixture isfiltered and the filtrate is evaporated to dryness. The residue isrecrystallized from benzene to give 5.25 grams of 1-N,N-dimethylcarbamyl-3-formamidopyrazole, M.P. 7578 C.

The compound of this example has significant analgesic activity. It isconveniently formulated in 2% :by weight concentration in water togetherwith a flavoring agent and can be taken orally in doses of from 10 to 50milligrams each every 4 to 6 hours as needed as a codeine substitute forrelief from pain.

It can also be formulated as a tablet containing from 2.5 to 50milligram amounts, from 1-4% by weight of gelatin and from 0.5 to 1.5%by weight of a lubricant such as magnesium stearate or talc, andmannitol as a filler.

By the foregoing procedures the following exemplary compounds can beobtained:

Product Example:

8 253-formamido-4-chlorol-N-methyl-N-ethylcarbamylpyrazole26-3-formamido-4-bromol-N-rnethyl-N-diethylarninoethylcarbamylpyrazole27-3-formamido-4-methyl-1-methyl-N-ethoxypropylthiocarbamylpyrazole283-acetarnido-4chloro-1-N,N-dimethylcarbamylpyrazole29-3-acetamido-4-methyl-l-N,N-dimethylcarbamylpyrazole30-3-acetamido-4-chloro- 1 -N,N-dimethylthiocarbamylpyrazole313-acetamido-4-methyl-1-N,N-dimethylthiocarbamylpyrazole323-acetamido-4-chloro- 1 -N-mcthyl-N-ethyl carbamylpyrazole 3 33-acetamido-4-chloro- 1 -N-methyl-N-ethylthiocarb amylpyrazole 343-acetamido-4-methyl-1-N-rnethyl-N-ethylcarbamylpyrazole 35-3-acetarnido-4-methyl-1-N-methyl-N-ethylthiocarbamylpyrazole 36-3-propionamido-1-N,N-dimethylcarmabylpyrazole 3 73-propionamide-1-N,N-dimethylthiocarbamylpyrazole 3 83'propionamido-4-bromo-l -N,N-dimethylcarbamylpyrazole 393-propionamido-4-chloro-1-N,N-dimethylcarbamylpyrazole 403-propionamido-4-methyl-1-N,N-dimethylcarb amylpyrazole41-3-propionamido-4-trifluoromethyl-LN-methyl-N-sec-butylcarbamylpyrazole42-3-formamido-4-chlorol-N-methyl-N-n-propylcarbamylpyrazole 43-3-formamido-4-chloro-1-N-methyl-N-n-propylthiocarbamylpyrazole44-3-formamido-4-methyl-l-N-methyl-N-n-propylcarbamylpyrazole45--3-formarnido-4-bromo- 1 -N-methyl-N-n-propylcarbamylpyrazole463-formamido-4-br0mo-1-N-methyl-N-isopropylcarbamylpyrazole473-formamido-4-chloro-l-N-methyl-N-isopropylcarbamylpyrazole483-acetamido-4-chloro-1N-methyl-N-methoxy ethylcarbarnylpyrazole 493-formamido-4-chloro-1-N-methyl-N-dimethylaminocarbarnylpyrazole503-formamido-4-brom0- l-N-methyl-N-isobutylcarbamylpyrazole51-3-propionamid o-4-methyl-l-N-methyl-N-allylcarbamylpyrazole 52-3-arnino-4-n-propyl-1-N-methyl-N-diethylamin0- ethylcarbamylpy-razoleExample 53.-3-acetamido-1-N-piperidinocarbonylpyrazole A mixture of 12.5grams (0.1 mole) of 3-acetamidopyrazole and 4.7 grams of sodium hydride(53% in oil) in 200 milliliters of dimethoxy ethane is stirred andrefiuxed for 30 minutes. Pentamethylenecarbamoyl chloride (15.7 grams,0.1 mole) is added in portions, and the mixture is refluxed 8 hours withstirring. The hot reaction mixture is filtered and the precipitatewashed with ethyl acetate. The filtrate is cooled in ice and theprecipitate is collected, yield 4.4 grams, M.P. 188-197" C. Theprecipitate first obtained is washed with water to remove the sodiumchloride and dried, yield 14.3 grams, M.P. 202- 204 C. A portion of thelatter is recrystallized twice from dioxane to give pure3-acetarnido-1-N-piperidinocarbonylpyrazole, M.P. 207.5-208.5 C.

Annlysis.Calcd. for C I-1 N 0 C, 55.9; H, 6.8. Found: C, 56.0; H, 7.0.

This compound can be formulated and used in 5, 10 and 50 milligramamounts in standard two piece hard gelatin capsules containing cornstarch as a diluent.

The preceding example is repeated substituting other substitutedpyrazoles and substituted carbamoyl and thiocarbamoyl chlorides for thereactants of that example to obtain the following compounds:

Example: Product 54-3 -amino-1-N-rnorpholinocarbonylpyrazole 55-3-acetamido- 1-N-pyrrolidinocarbonylpyrazole56-3-formamido-1-N-piperidinocarbonylpyrazole 57-3-formamidol-N-dehydropiperidinocarbonylpyrazole 58-3 -acetamido- 1-Ndehydropiperidinocarbonylpyrazole 59-3-formamido-1-N-azabicyclononylcarbonylpyrazole60-3-acetamido-1-N-(3,4-dimethylpiperidino)- carbonylpyrazole 61-3-acetamido-1-N-p-tolylethylpiperidinocarbonylpyrazole 62-3-formamido-4-bromol-N-m-methylpiperidinocarbonylpyrazole63-3-acetamido-4-chloro- 1-N-p-trifluorornethylpiperidinocarbonylpyrazole 64-3-acetamido-4-chloro-1 -N-p-ethylpiperidino (thiocarbonyl) pyrazole 65-3-propionamido-4-bromo- 1 -N- [p- (n-butyl piperidino](thiocarbonyDpyrazole 66-3 -acetamido-4-methyll-N-o-methylpiperidino-(thiocarbonyl pyrazole 67-3-formamido-4-chloro- 1-N-p-benzylpiperidinocarbonylpyrazole 68-3 -acetamido-4-chlorol-N-(m-ethoxycarbonylpiperidino) carbonylpyrazole69-3-acetamido-4-chloro-1-N-dehydropiperidinocarbonylpyrazole 70-3-formamido-4-chloro-1-N-( 3-methyl-4-ethylpiperidino carb onylpyrazole 7l-3-acetamido-4-methyll -N-pyrrolidinocarbonylpyrazole 72-3-formamido-4-chloro-1 -N-p-methylpiperidino- (thiocarbonyl pyrazole73-3 -propionamido-4-isopropyll-N-p-isopropylpiperidinocarbonylpyrazole7 4-3-amino-4-fiuoro- 1 -N- p- (n-propyl piperidino] carbonylpyrazole75-3-acetamido-4-ethyll-N-phenethylpiperidinocarbonylpyrazole 76-3 -formamido-4-chlorol -N- (p-diethylaminoethyl piperidino) carbonylpyrazole77-3-acetamido-4-bromo- 1 -N- (p-pyrrolidinoethylpiperidinocarbonylpyrazole 78-3 -acetamido-4-methy1- 1 -N-(p-butoxycarbonylpiperidino) carbonylpyrazole 79-3-acetamido-4-chloro-1-N- [3,4-di(2-hydroxyethyl) piperidino]carbonylpyrazole 8-3-formamido-4-bromol-N-o-tolylethylpiperidinocarbonylpyrazole The aboveexamples can be repeated to obtain other compounds within the scope ofthis invention by appropriate selection of reactants as will be readilyunderstood in the art.

The invention claimed is:

1. A method for producing analgesia comprising administering to awarm-blooded animal an analgesically effective amount of a compound ofthe formula 10 where:

X is selected from the group consisting of oxygen and sulfur; A isselected from the group consisting of wherein R is methyl; and R isselected from the group consisting of alkyl of 1 through 6 carbons Wherethe alkyl is joined to the carbamyl nitrogen by a carbon selected fromthe group consisting of a primary and a secondary carbon of said alkyl;alken-2-yl of 3 through 6 carbons where the alken- 2-yl is joined to thecarbamyl nitrogen by a carbon selected from the group consisting of aprimary and a secondary carbon of said *alken-2-yl; alkoxyalkyl of 2through 6 total carbons; dimethylamino; and dialkylaminoalkyl where eachof the alkyl groups in the dialkyl portion has 1 through 2 carbons andthe remaining alkyl group has 1 through 4 carbons with a total of 3through 7 in said dialkylaminoalkyl group;

morpholino;

pyrrolidino;

piperidino;

dehydropiperidino;

azabicyclononidino;- and a substituted piperidino group of the structurewherein Y is selected from the group consisting of hydrogen and methyl,Y is selected from the group consisting of hydrogen, methyl, ethyl and-COOR Where R is alkyl of 1 through 4 carbons; and Y is selected fromthe group consisting of hydrogen, alkyl of 1 through 6 carbons,hydroxyalkyl of 2 through 6 carbons, trifiuoromethyl, -COOR Where R isalkyl of 1 through 4 carbons, dialkylaminoalkyl of 3 through 7 carbonswhere each of the alkyl groups in the dialkyl portion has 1 through 2carbons and the remaining alkyl group has 1 through 4 carbons,pyrrolidinomethyl, and hydrocarbon aralkyl of 7 through 9 carbons;

R is selected from the group consisting of hydrogen,

formyl, acetyl, propionyl; and

R is selected from the group consisting of hydrogen,

chlorine, bromine, fluorine, alkyl of 1 through 3 carbons, andtrifluoromethyl.

2. The method of claim 1 wherein the compound isl-N-(4-methylpiperidino)carbonyl 3(5) formamido-4- chloropyrazole.

3. The method of claim 1 wherein the compound is 1-N-(4-methylpiperidino)carbonyl-3(5) formamido 4- methylpyrazole.

4. The method of claim 1 wherein the compound isl-N-(4-methylpiperidino)carbonyl 3(5) acetamid0-4- chlor-opyrazole.

5. The method of claim 1 wherein the compound is 1-N-(4-methylpiperidino)carbonyl 3(5) acetamido 4- methylpyrazole.

6. The method of claim 1 wherein the compound is l-N(4-methylypiperidino)carbonyl 3(5) propionamido-4-chloropyrazole.

7. The method of claim 1 wherein the compound is 1-N-(4-methylpiperidino)carbonyl 3 (5) propionamide-4- met-hylpyrazole.

8. The method of claim 1 wherein the compound is 1- N,N-dimethylcarbamyl3(5) fiorrnamidopyrazole.

9. The method of claim 1 wherein the compound is3(5)-acetamido-1-N,N-dimethylcarbamylpyrazole.

10. The method of claim 1 wherein the compound is 1- 11N-methyl-N-isopropylcarbamyl 3(5) formamidopyra- Zole.

11. The method of claim 1 wherein the compound is3(5)-acetamido-l-N-methyl N isopropylcarbamylpyrazole.

12. The method of claim 1 wherein the compound is 1-N-sec-butyl-N-methylcarbamyl 3(5) formamidopyrazole.

13. The method of claim 1 wherein the compound is3(5)-acetamido-1-N-secbutyl N methylcarbamylpyrazole.

14. A composition comprising an analgesically effective amount of acompound of the formula wherein R is methyl; and R is selected from thegroup consisting of alkyl of 1 through 6 carbons where the alkyl isjoined to the carbamyl nitrogen by a carbon selected from the groupconsisting of a primary and a secondary carbon of said alkyl; alken-2-yl of 3 through 6 carbons where the alken-2-yl is joined to thecarbamyl nitrogen by a carbon selected from the group consisting of aprimary and a secondary carbon of said alken-Z-yl; alkoxyalkyl of 2through 6 total carbons; diethylamino; and dialkylaminoalkyl where eachof the alkyl groups in the dialkyl portion has 1 through 2 carbons andthe remaining alkyl group has 1 through 4 carbons with a total of 3through 7 in said dialkylaminoalkyl group;

morpholino;

pyrrolidino',

piperidino;

dehydropiperidino; azabicyclononidino; and a substituted piperidinogroup of the structure wherein Y is selected from the group consistingof hydrogen and methyl, Y is selected from the group consisting ofhydrogen, methyl, ethyl and -COOR where R is alkyl of 1 through 4carbons; and Y is selected from the group consisting of hydrogen, alkylof 1 through 6 carbons, hydroxyalkyl of 2 through 6 carbons,trifluoromethyl, -COOR where R is alkyl of 1 through 4 carbons,dialkylaminoalkyl of 3 through 7 carbons where each of the alkyl groupsin the dialkyl portion has 1 through 2 carbons and the remaining alkylgroup has 1 through 4 carbons, pyrrolidinomethyl, and hydrocarbonaralkyl of 7 through 9 carbons;

R is selected from the group consisting of hydrogen,

forrnyl, acetyl, propionyl; and

R is selected from the group consisting of hydrogen,

chlorine, bromine, fluorine, alkyl of 1 through 3 carhons, andtrifluoromethyl; and from 25 to 90% of a non-toxic pharmaceuticalcarrier for said compound.

15. A tablet composition comprising an analgesically effective amount ofa compound defined in claim 14, from 1 to 4% by weight of gelatin, from0.5 to 1.5% by weight of magnesium stearate, and mannitol as a filler.

16. An orally ingestible gelatin capsule containing 2.5 to milligrams ofa compound defined in claim 14 and from to 99% by weight of a non-toxicsolid filler selected from the group consisting of lactose, corn starchand mannitol.

References Cited UNITED STATES PATENTS 3,308,130 -3/1967 Bousquet 16765ALBERT T. MEYERS, Primary Examiner.

JULIAN S. LEVI'IT, Examiner.

S. I. FRIEDMAN, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,362,877 January 9, 1968 Clifford L. Dickinson, Jr.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 11, line 38, for "diethylamino" read dlmethylamino Signed andsealed this 8th day of April 1969.

(SEAL) Attest:

EDWARD J. BRENNER Commissioner of Patents Edward M. Fletcher, Jr.Attesting Officer

1. A METHOD FOR PRODUCING ANALGESIA COMPRISING ADMINISTERING TO AWARM-BLOODED ANIMAL AN ANAGESICALLY EFFECTIVE AMOUNT OF A COMPOUND OFTHE FORMULA